Process for the preparation of 17(20)-21-al pregnenes



United States Patent 3,374,253 1 PROCESS FOR THE PREPARATION OF17(20)-21-AL PREGNENES John H. Fried, Palo Alto, Calif., assignor toSyntex Corporation, Panama, Panama, a corporation of Panama No Drawing.Filed Apr. 25, 1966, Ser. No. 544,855

Claims. (Cl. 260--397.3)

This invention relates to a novel process for the preparation ofcyclopentanophenanthrene derivatives.

More particularly, this invention relates to a novel process for thepreparation of A -21-al pregnanes from the corresponding l7-ketosteroid.The A -21-al pregnanes prepared by the present invention are valuableintermediates for the preparation of pharmacologically importantcompounds such as the corticoids, see for example US. Patents 2,577,018,2,683,153, 2,732,384, 3,120,518, and 3,165,444.

Prior to the present invention, the preparation of A -21-al pregnanesfrom 17-ketosteroids was accomplished by, for example, reacting thel7-ketosteroid with a Grignard derivative of ethoxyacetylene to obtainthe corresponding 17a-ethoxyethynyl-17,8-hydroxy steroid which was thenselectively hydrogenated to the corresponding17a-ethoxyvinyl-17,8-hydroxy compound followed by treatment withsulfuric acid in dioxane to obtain the unsaturated aldehyde, that is,the A -21-al pregnane. This method and other prior art methods involveseveral steps which create undesired side products and cause thepreparation of A -21-al pregnanes to be unnecessarily complex.

The primary object of the present invention is to provide a process forthe preparation of A -21-al pregnanes which overcomes the aforementioneddisadvantages. Other objects and advantages will become apparent as theinvention is hereinafter described in detail.

In accordance with the. present invention, A -2l-al pregnanes areprepared by the reaction of a 17-ketosteroid with at least one molarequivalent of LiCH -CH=NR, wherein R represents a lower alkyl containingfrom 1 to 6 carbon atoms or a cycloalkyl group containing from 3 to 7carbon atoms such as methyl, ethyl, isopropyl, butyl, cyclohexyl,cyclopentyl and the like, in an ether solvent medium followed by acidhydrolysis.

The novel process of the present invention can be illustrated as followsusing only the applicable D-ring of the steroid nucleus.

In the above formulas, R represents a lower alkyl or cycloalkyl group asdefined hereinabove and R represents a lower alkyl group containing from1 to 4 carbon atoms, that is methyl, ethyl, propyl or butyl.

In practicing the novel process outlined above, the j 3,374,253 PatentedMar. 19, 1968 II to acid hydrolysis which furnishes the desiredunsaturated aldehyde steroid IH. This step may be accomplished by addinga source of hydrogen ions to the reaction mixture resulting from thefirst step of the process. As a source of hydrogen ions, there may beemployed water or water containing a small amount of an inorganic or ahydrocarbon carboxylic acid such as hydrochloric acid, sulfuric acid,acetic acid, and the like, preferably aqueous acetic acid, at roomtemperature or above.

The lithium imines characterized by the formula LiCH CH=NR, as describedhereinabove, may be prepared in theconventional manner as by thereaction of acetaldehyde with, e.g. cyclohexylamine to obtain the Schitfbase. The Schiif base and a lithium alkylarnide, e.g. lithiumdiisopropylamide are then dissolved in ether and allowed to stand atroom temperature for from 1 to 6 hours furnishing the desired lithiumimine. Lithium alkylamides may be prepared, for example, by the reactionof an alkyl amine with lithium hydride.

The expression l7-ketosteroids as used herein and in the appended claimsis understood to refer to steroids having an oxo function at thecarbon-17 position. The steroid nucleus may be saturated, unsaturated oraromatic. Typical 17-ketosteroids which may be employed in the processof the present invention are 3B-hydroxyandrost-5-en-l7-one, BB-hydroxy5a androstan-17-one, 3u-hydroxy-5B-androstan-l7-one, 3-hydroxy-or3-methoxyestra-1,3,5(10)-trien-l7-one, 3-hydroxyor 3-methoxyestra-1,3,510),9( 11)-tetraen-17-one, 3-methoxyestra-2,5 10)-dien-17-one, 3,1lfl-dihydroxyestra-2,5(10)-dien-l7- one 3-methyl ether,3,3-cycloalkylenedioxyandrost-S-ene- 11,17-dione,3-ethoxyandrosta-3,5-diene-11,17-dione, 3-ethoxy-l8-ethylandrosta-3,5-diene-11,17-dione,3,11a-dihydroxyandrosta-3,5-dien-17-one 3-ethyl ether, and thecorresponding compounds having a free 3-hydroxyl function or the acylatethereof. In the case of the acylates, it is preferred to employ the morestable esters such as benzoate, and the like.

The following detailed examples are provided to illustrate the presentinvention but not to limit the scope thereof.

Example 1 A mixture of 30 grams of 3fl-hydroXyandrost-5-en-17- one, 2.2molar equivalents of 2-1ithioethyl-N-cyclohexyliand 200 ml. of diethylether is stirred at room temperature for about 24 hours. Thereafter, thereaction mixture is poured into two liters of water containing about 25ml. of acetic acid, stirred and then filtered. The product is thenwashed with water and dried affording 3fl-hydroxypregna-5,17(20)-dien-21-al which may be purified by chromatography orcrystallization from acetonezhexane.

' Example 2 A mixture of 35 grams of 3-methoxyestra-2,5(l0)-dien-l7-one, 1.2 molar equivalents of 2-lithioethy1-N-cyclohexylimine,and 240 ml. of diethyl ether is stirred at room temperature for about 24hours. Then, the reaction mixture is poured into two liters of watercontaining about 30 ml. of acetic acid, stirred, and filtered. The solidprodnot is washed with water and dried affording 3-oxo-19-nor-pregna-4,17(20)-dien-2l-al.

Example 3 A mixture of 30 grams of 3-methoxyestra-1,3,5(10)-trien-17-one, 1.2 molar equivalents of 2 lithioethyl-N- cyelohexylimine,and 200 ml. of diethyl ether is stirred for about 20 hours at roomtemperature. Thereafter, the

3 reaction mixture is poured into about two liters of water containingabout 25 ml. of acetic acid and filtered. The solid product is washedwith water and dried to afford 3- methoxypregna-1,3,5 10 17(20-tetraen-21-al.

Example 4 A mixture of 30 grams of 3-ethoxyandrosta-3,S-diene-11,17-dione, 1.2 molar equivalents of 2-lithioethyl-N- ethylimine and175 ml. of diethyl ether is stirred at room temperature for about 24hours. Thereafter, the reaction mixture is poured into two liters ofwater containing about 30 ml. of acetic acid and filtered. The solidreaction product is washed with water and dried to afford3,11-dioxo-pregna- 4,l7(20)-dien-2l-al.

Example 5 By repeating the procedure of Example 1, Ste-hydroxy-5a-androstan-17-one is converted into3/3-hydroxy-5apregn-l7(20)-en-21-al.

Similarly, 3a-hydroxy-5/3-androstan-17-one is converted into thecorresponding 3a-hydroxy-5fi-pregn-17(20)-en- 21-al.

Example 6 By repeating the procedure of Example 2,3/3-tetrahydropyran-2-yloxy-5u-androstan-17-one is transformed into thecorresponding 3fl-hydroxy-5a-pregn-l7(20)-en-21-al.

Likewise, the tetrahydropyranyl ether of 3u-hydroxy-5/3-androstan-17-one and 3-hydroxyestra-1,3,5(10)-trien- 17-one areconverted into 3a-hydroxy-5fl-pregn-17(20)-en- 21-al and3-hydroxypregna-l,3,5(10),17(20)-tetraen-21- 9.1, respectively.

The tetrahydropyranyl ether starting materials are prepared by treatingthe corresponding free hydroxyl com- 4 pound with dihydropyran in thepresence of an acid catalyst, see for example, U.S. Patent 2,637,728.

What is claimed is:

1. A process for the preparation of A -2l-al pregnanes which comprisesreacting a 17-ketosteroid with at least one molar equivalent of LiCH CHNR, wherein R is selected from the group consisting of a lower alkylgroup containing from 1 to 6 carbon atoms and a cycloalkyl groupcontaining from 3 to 7 carbon atoms, in an ether solvent medium andsubjecting the thus-formed compound to acid hydrolysis.

2. A process according to claim 1 wherein R is cyclohexyl.

3. A process according to claim 1 wherein R is cyclo- -hexyl and saidether solvent is diethyl ether.

4. A process according to claim 1 wherein R is cyclohexyl, said ether isdiethyl ether, and said acid hydrolysis is accomplished by the use ofaqueous acetic acid.

5. A process according to claim 4 wherein said 17- keto-steroid is3-ethoxyandrosta-3,5-dien-l7-one.

6. A process according to claim 4 wherein said 17-ketosteroid is3-metl1oxyestra-1,3,5(10)-trien-l7-one.

7. A process according to claim 4 wherein said l7-ketosteroid is3-ethoxy-l1fl-hydroxyandrosta-3,S-dien-17-one.

8. A process according to claim 4 wherein said 17-ketosteroid is3-ethoxyandrosta-3,S-diene-11,17-dione.

9. A process according to claim 4 wherein said 17-ket0- steroid is3u-hydroXy-Sfi-andmstan-17-one.

10. A process according to claim 4 wherein said 17-ketosteroid is 3fl-hydroxy-S a-androstan-17-one.

References Cited UNITED STATES PATENTS 3,318,917 5/1967 Benn 260397.1

LEWIS GOTTS, Primary Examiner.

T. M. MESHBESHER, Assistant Examiner.

1. A PROCESS FOR THE PREPARATION OF $17(20)-21-AL PREGNANES WHICHCOMPRISES REACTING A 17-KETOSTEROID WITH AT LEAST ONE MOLAR EQUIVALENTOF LICH2-CH=N-R, WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF ALOWER ALKYL GROUP CONTAINING FROM 1 TO 6 CARBON ATOMS AND A CYCLOALKYLGROUP CONTAINING FROM 3 TO 7 CARBON ATOMS, IN AN ETHER SOLVENT MEDIUMAND SUBJECTING THE THUS-FORMED COMPOUND TO ACID HYDROLYSIS.